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Elevated androgens and insulin resistance in PCOS: the 'Chicken and the egg' and the importance of thorough evaluation of obese and nonobese patients.

Polycystic ovarian syndrome (PC05) is the most common endocrine disorder found in women of reproductive age. Most clinicians and many patients are familiar with this syndrome, or duster of symptoms, as it affects an estimated 10% or more of premenopausal women depending on the diagnostic criteria used. (1), (2) Common presenting symptoms include irregular ovulation that often results in irregular or absent menstrual cycles, infertility, hirsutism, acne, alopecia, obesity, and blood sugar dysregulation.

There has been some variation in the parameters for diagnosis since first mention of this condition by Stein and Leventhal in 1935; however, the most currently used definition was established in 2003 at a symposium in Rotterdam, Netherlands. The consensus of both the European Society of Human Reproduction and Embryology (ESHRE) and the American Society for Reproductive Medicine (ASRM) coming out of this conference, known as the Rotterdam criteria, defines PCOS as the presence of 2 out of the 3 following criteria (3):

* infrequent or absent ovulation (oligoovulation or anovulation)

* elevated androgens evident in clinical presentation (hirstuism, acne, etc.) or upon laboratory findings

* presence of 12 or more follicles measuring 2 to 9 mm in diameter ovarian cysts on imaging

Though not part of these criteria or any other official definition of PCOS, there is a strong comorbidity with PCOS and obesity. More than 50010 of PCOS patients are overweight or obese, and an increase in obesity has been linked to an increase in the prevalence of PCOS. (4), (5) Additionally, there is a strong correlation between women with PCOS and abnormalities in insulin utility and there is ample evidence to support this as an important component of the pathogenesis of the disorder. (6), (7) The correlation between an increase in obesity and increased incidence of PCOS may likely be clue to increased hyperinsulinemia in obese populations, and the Rotterdam criteria indicate that obese women with PCOS should be screened for metabolic syndrome. (8) It's imperative however, that clinicians not overlook the role of insulin resistance and metabolic syndrome in PCOS patients who are not obese, as they are also likely to have abnormalities in glucose metabolism. Despite this relationship being discussed in literature for decades, many anovulatory or hirsute patients are not immediately evaluated for hyperinsulinemia if they have a body mass index (BMI) that is not out of range. (9), (10), (12) Because there is evidence that increased androgens can promote insulin resistance and that the inverse, hyperinsulinemia may promote hyperandrogenism, it is difficult to know which comes first and highlights the importance of a complete laboratory analysis of all patients presenting with "PCOS-like symptoms" regardless of their weight, as all women with PCOS have an increased risk of developing diabetes later in life. (11), (12)

Insulin Stimulates Androgen Production

Insulin stimulates androgen production through a number of mechanisms, and understanding these nuances may allow us to direct treatment accordingly.

1. Human ovaries have insulin receptors, and in vitro studies have shown that insulin can have a direct effect on androgen production in stroma cells of the ovaries. (13)

2. Insulin decreases the serum level of sex hormone binding globulin (SHBG), the primary carrier protein bound to testosterone in serum. When SHBG levels decrease, this allows circulation of more testosterone that is unbound, or free to interact with target tissues, thus amplifying the effect of testosterone. (14)

3. Insulin-like growth factors (IGF), like insulin, can stimulate ovarian growth and androgen synthesis, and IGF-1 may work with insulin both directly on the ovary and in cooperation with lutenizing hormone (LH) to produce androgen hormones. (15) Similar to its effect on SHBG, insulin also reduces bioactive levels of the primary binding protein for IGF (IGFBP-1), rendering more IGF available for action at target tissues. (16)

4. Insulin may act directly on the anterior pituitary in the regulation of gonadotropin release; namely, increasing luteinizing hormone (LH). Disproportionate stimulation of LH in - relation to follicle stimulating hormone (FSH) may lead to a thickening of the ovarian stroma and cause a consequent increase in androgen production from the ovary directly. (17)

5. In addition to increased androgen synthesis in the ovary, there is a significant increase in adrenal androgen levels seen in many women with PCOS. (18), (19) Elevations in DHEA and androstenedione can both have a direct androgenic effect and feed elevated testosterone levels through the steroid synthesis cascade. The adrenal component to androgen excess may be more prevalent in younger and leaner patients, making the analysis of adrenal androgens an especially important clinical consideration in nonobese PCOS or suspected PCOS patients. (20)

Elevations in Androgens Contribute to Insulin Resistance

As with any classic causality dilemma, it is difficult to know if elevations in androgen hormones are a result of insulin resistance through one of the mechanisms outlined above, or if the presence of high androgens contributes to decreased insulin sensitivity in the first place. Though not as well studied as the inverse, there is evidence to show that elevations in sex hormones including androgens may affect insulin sensitivity. In studies of ovariectomizecl rats, the administration of testosterone resulted in severe insulin resistance in approximately 50010 of the subjects. (21) Additional studies on the effects of supraphysiologic doses given to transsexual patients undergoing hormone treatment indicated no change in glucose production, but a diminished peripheral glucose uptake, suggesting that elevations in androgens can induce insulin resistance. (22)

In a more tangential relationship, elevated circulating levels of estrogens have also been shown to influence a pattern of peripheral insulin resistance. (11) Androgens can be converted to estrogens via the aromatase enzyme; therefore this may be another mechanism affecting insulin resistance in the PCOS population. Additionally, long-term use of oral contraception pills (a common conventional treatment for PCOS) may also contribute to insulin resistance. (23)

There are likely several contributing factors to the etiology of PCOS beyond insulin resistance and high androgens, including genetic factors and environmental influences. (24) Other common theories suggest that there is a primary disorder of the gonadotropins resulting in an initial increase in LH that stimulates theca cells in the ovary to produce androgens or that the chief defect is in the steroidogenesis within the ovary and adrenal glands. (25), (26) Irrespective of whether the primary event in PCOS is an increase in androgen hormones (that we know can contribute to insulin resistance) or a principal error in blood sugar metabolism (that leads to androgen stimulation), identifying and adjusting for insulin usage and elevations in androgens can be an effective way to manage the presenting symptoms and control sequelae of PCOS. (27)

Clinical Applications

Regardless of the patient's BMI, those who present with symptoms of PCOS, including oligo- or amenorrhea, infertility, acne, hirsutism, or ovarian cysts, should receive a thorough workup including evaluation of ovarian and adrenal androgen hormones in addition to an assessment of insulin utility. Treatment of either elevations in androgens or insulin resistance can slow the pathophysiology of the disease and prevent development of more serious conditions, including type 2 diabetes.

There isn't a definitive measurement for insulin resistance; however, a fasting glucose level may not be sufficiently sensitive; a glucose tolerance test or fasting insulin level will provide more insight. Measurements of androgen hormones should include the free or unbound fraction of testosterone, whether in saliva or serum, to correctly assess the hormone's influence independent of fluctuating SHBG levels. It's important to include an assessment for adrenal androgens as well: a DHEA sulfate level in serum or DHEA in saliva.

Laboratory Tests for PCOS

Tests to evaluate    * Fasting insulin level
insulin resistance   * 1 and 2 hour post-parandial glucose
                      tolerance test
                     * 1 and 2 hour post-parandial insulin
                     tolerance test
                     * Hemaglobin A1C Tests to evaluate
                     insulin resistance

Measure of           * Free and total testosterone
androgen hormones    in serum or salivary testosterone level
                     * DHEA-S in serum or salivary DHEA level
                     * Serum androstenedione
                     * Serum SHBG

Table 1: Suggested laboratory tests for obese and
non-obese PCOS patients


When it comes to treatment for these patients, controlling blood sugar utilization and optimizing insulin receptor function is important for all. There are many studies showing the benefits of weight loss for patients who are overweight or obese, and this should be a primary goal for this population, as visceral adipose cells are more insulin resistant than other cells in the body. (28), (29)For both overweight and normal weight PCOS patients, following a diet that prevents radical fluctuations in blood sugar is optimal. Women with PCOS have shown a marked compensatory increase in blood insulin levels after carbohydrate intake, and therefore consuming foods with a low glycemic index is recommended. (30), (31) Exercise stimulates glucose transport in peripheral tissues and skeletal muscle and should be an important part of any treatment plan. (32) In addition to lifestyle changes including diet and exercise programs, a number of medications and supplements may help with insulin utility and blood sugar balancing:

* Metformin is the most commonly used and extensively studied insulin-sensitizing agent used with PCOS and is thought to decrease hepatic output of glucose as well as increase insulin sensitivity in peripheral tissues. (11), (33)

* N-acetylcysteine, a derivative of the amino acid L-cysteine and a precursor to the antioxidant glutathione, is commonly used for detoxification support and has also been shown to have effects on hyperandrogenism and hyperinsulinemia comparable to those of metformin. (34)

* The same fat-soluble vitamin that we've long looked to for bone health, cancer prevention, and optimizing immune function also plays an important role in the pathogenesis of insulin resistance, as vitamin D replacement can improve insulin utility at the receptor level. (35), (36)

* Chromium is an essential trace element that is an important component of glucose tolerance factor, a complex of amino acids and chromium that works with insulin to facilitate glucose uptake into the cells. Chromium deficiency has been associated with diabetes and insulin resistance, and supplementation has been shown to improve blood sugar util ization. (37), (38)

In addition to controlling insulin utility and treating insulin resistance, which will ultimately result in lowering androgen levels due to a reduction in stimulation, there are several direct treatments for blocking or lowering androgens that may reduce the induction of insulin resistance, including:

* spironolactone, an aldosterone antagonist and diuretic, inhibits ovarian and adrenal steroidogenesis and works to block the androgen receptor (39);

* epigallocatechin-3-gal late, an extract from green tea, has been shown to modulate the production and action of androgens as well as other hormonest

* licorice (of course, the plant Glycyrrhiza glabra, not the candy) can reduce serum testosterone levels by blocking the 17-hydroxysteroid dehydrogenase and 17-20 lyase enzymes; however, it should be used with caution in patients who have hypertension, as one common side effect is hypokalemic hypertension. (41), (42)

A thorough analysis of hormone levels and determination of blood sugar levels and insulin utilization should be done in all patients presenting with symptoms of PCOS, regardless of their weight. A proactive treatment approach that addresses either side of the elevated androgen/insulin resistance picture will not only ameliorate many symptoms that the patient is experiencing, but work to prevent development of more significant illness, including diabetes and cardiovascular disease.

Notes

(1.) Teede H, Deeks A, Moran L. Polycystic ovary syndrome: a complex condition with psychological, reproductive and metabolic manifestations that impacts on health across the lifespan. BMC Medicine 2010;8:41.

(2.) Broekmans FL Knauff EA, Valkenburg 0, et at. PCOS according to the Rotterdam consensus criteria: Change in prevalence among WHO-II anovulation and association with metabolic factors. 8I0G. 2006; 113(10):1210-1217.

(3.) Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovarian syndrome. Feral 2004;81(1):19-25.

(4.) Ojaniemi M, Pugeat M. An adolescent with polycystic ovarian syndrome. Eur J Endocrinol. 2006;155:S149-S152.

(5.) Ehrmann DA. Polycystic ovary syndrome. N Engl J Med. 2005;352:1223-1236.

(6.) Dunaif A, Segal KR, Futterweit W, Dobrjansky A. Profound peripheral insulin resistance, independent of obesity, in polycystic ovary syndrome. Diabetes. 1989;38:1165-1174.

(7.) Dunaif A. Insulin resistance and the polycystic ovary syndrome: mechanism and implications for pathogenesis. Endocr Rev. 1997;18:774-800.

(8.) Cebeci F, Onsun N, Men M. Insulin resistance in women with hirsutism. Arch Med Sci. 2012;8(2):342-346.

(9.) Burghen GA, Givens JR, Kitabchi AE. Correlation of hyperandrogenism with hyperinsulinism in polycystic ovarian disease. I Clin Endocrinol Metab. 1980;50:113-116.

(10.) Pasquali R, Casimirri E, Venturoli 5, et al. Insulin resistance in patients with polycystic ovaries: its relationship to body weight and androgen levels. Acta Endocrinol. 1983;104:110-116.

(11.) Livingstone C. Collison M. Sex steroids and insulin resistance. Clin Sci. 2002;102:151-166.

(12.) Chang RI, Nakamura RM, Judd H L, Kaplan SA. Insulin resistance in non-obese patients with polycystic ovarian disease. I Clin Endocrinol. Metab. 1983;57:356-59.

(13.) Barbieri RL, Makris A, Randall RW, et al. Insulin stimulates androgen accumulation in incubations of ovarian stroma obtained from women with hyperandrogenism. Clin. Endocrinol Metab. 1986;62:904-910.

(14.) Nestler 1E, Powers LP, Matt DW, et at. A direct effect of hyperinsulinemia on serum sex hormone-binding globulin levels in obese women with the polycystic ovary syndrome. J Clin Endocrinol Metab. 1991;72:83-89.

(15.) Bergh C, Carlsson B, Olsson JH, Selleskog U, Hillensjo, T. Regulation of androgen production in cultured human thecal cells by insulin-like growth factor I and insulin. Fertil Steril. 1993:59;323-331.

(16.) Conway GS, Jacobs HS, Holly JM, Wass IA. Effects of luteinizing hormone, insulin, insulin-like growth factor-I and insulin-like growth factor small binding protein-1 in the polycystic ovary syndrome. Clin Endocrinol. 1990:33;593-603.

(17.) Adashi EY, Hsueh AJW, Yen SSC. Insulin enhancement of luteinizing hormone and follicle-stimulating hormone release by cultured pituitary cells. Endocrinology. 1981;108(4):1441-1449.

(18.) Cinar N, Harmanci A, Aksoy DY, et al. Adrenocortical steroid response to ACTH in different phenotypes of non-obese polycystic ovary syndrome. I Ovarian Res. 2012;5:42.

(19.) Carmina E. Ovarian and adrenal hyperadnrogenism. Ann N Y Acad Sci. 2006:1092130-137.

(20.) Mor 'an C, Knochenhauer E, Boots LR, Azziz R. Adrenal androgen excess in hyperandrogenism: relation to age and body mass. Ferri! Steril. 1999;71(4)671-674.

(21.) Holmang A, Svedberg J, Jennische E, Bjorntorp P. Effects of testosterone on muscle insulin sensitivity and morphology in female rats. Am J Physiol. 1993;259:E555--E560.

(22.) Polderman KH, Gooren LI, Asschernan H et al. Induction of insulin resistance by androgens and estrogens. Clin Endocrinol Metab. 1994;79(11:265271.

(23.) Godsland IF, Walton C, Felton C et al. Insulin resistance, secretion, and metabolism in users of oral contraceptives. J Clin Endocrinol Metab. 1992;74(1):64-70.

(24.) Kandaraki E, Chatzigeorgiou A, Livadas S et al. Endocrine disruptors and polycystic ovary syndrome (PCOS); elevated serum levels of bisphenol A in women with PCOS. J Clin Endocrinol Metab. 2011;96(3):E480--E484.

(25.) Rebar R, Judd HL, Yen SS, Rakoff I, Vandenberg G, Naftolin F. Characterization of the inappropriate gonadotropin secretion in polycystic ovary syndrome. I Clin Invest. 1976;57:1320-1329.

(26.) Nelson VL, Legro RS, Strauss JF, Ill, McAllister JM. Augmented androgen production is a stable steroidogenic phenotype of propagated theca cells from polycystic ovaries. Mel Endocrinol. 1999;13:946-957.

(27.) Corbould A. Effects of androgens on insulin action in women: is androgen excess a component of female metabolic syndrome? Diabetes Metab Res Rev. 2008;24(7):520-32.

(28.) Roessler KK, Birkebaek C, Ravn P et al. Effects of exercise and group counseling on body composition and VO(2max) in overweight women with polycystic ovary syndrome. Acta Obstet Gynecol Scand. 2012.

(29.) Kiddy DS, Hamilton.Fairley D, Bush A, et al. Improvement in endocrine and ovarian function during dietary treatment of obese women with polycystic ovary syndrome. an Endocrinol (Oxf).1992;36(1):105-111.

(30.) Marsh KA, Steinbeck KS, Atkinson FS et al. Effect of a low glycemic index compared with a conventional healthy diet on polycystic ovary syndrome. Am 1 Clin Nutr. 2010;92(1):83-92.

(31.) Soloman TP, Haus JM, Kelly KR et al. A low-glycemic index diet combined with exercise reduces insulin resistance, postprandial hyperinsulinemia, and glucose-dependent insulinotropic polypeptide responses in obese, prediabetic humans. Am I Clin Nur. 2010;92(6):1359-1368.

(32.) Goodyear LJ, Kahn BB. Exercise, glucose transport and insulin sensitivity. Annu Rev Med. 1998;49:235-261.

(33.) Seli E, Duleba AJ. Treatment of PCOS with metformin and other insulin-sensitizing agents. Curr Diab Rep. 2004;4(1):69-75.

(34.) Oner G, Muderris II. Clinical, endocrine and metabolic effects of metformin vs. N-acetyl-cysteine in women with polycystic ovary syndrome. Euro 1 Obstet Gynecol Reprod Biol. 2011;159(1):127-131.

(35.) Patra SK, Nasrat H, Goswami B, Jain A. Vitamin D as a predictor of insulin resistance in polycystic ovarian syndrome. Diabetes Metab Syndr. 2012;6(3):146149.

(36.) Sung CC, Liao MG, Lu KC, Wu CC. Role of vitamin D in insulin resistance. J Biomed Biotechnol.. 2012;2012:634195.

(37.) Cefalu WT, Hu FB. Role of chromium in human health and in diabetes. Diabetes Care 2004;27:2741-2751.

(38.) Racek J, Trefil 1, Rajdl 0, Mudrovii V, Hunter 0, Senft V. Influence of chromium-enriched yeast on blood glucose and insulin variables, blood lipids, and markers of oxidative stress in subjects with type 2 diabetes mellitus. Biol Trace Elem Res. 2006;109(3):215-230.

(39.) Helfer EL, Miller IL, Rose LI. Side-effects of spironolactone therapy in the hirsute woman. J Clin Endocrinol Metab.1988;66:208-211.

(40.) Liao S. The medicinal action of androgens and green tea epigallocatechin gallate. Hong Kong Med J. 2001;7(4):369,-374.

(41.) Armanini D, Mattarello MI, Fiore C, et al. Licorice reduces serum testosterone in healthy women. Steroids. 2004;69(11-12):763-766.

(42.) N Armanini 0, Bonanni G, Palermo M, et al. Reduction of serum testosterone in men by licorice. N Engl J Med 1999;341:1158.

by Sara G. Wood, ND

Dr. Wood grew up in Colorado and obtained her undergraduate degree in biochemistry from Colorado College. An enthusiasm for science and a passion for people led her to medicine; and a desire to treat the cause of disease, not just the symptoms, led her to naturopathy. After completing her doctorate at the National College of Naturopathic Medicine, Dr. Wood stayed in Oregon and has a private practice focused on endocrine imbalance, digestive dysfunction, immune support, and cardiovascular health.

In addition to her clinical practice, Dr. Wood is a staff physician with Labrix Clinical Services Inc., where she educates physicians and health care providers around the country about hormonal balancing through development of educational materials, contributions to a webinar series, and lectures at local and national conferences. In 2008 she coauthored a book on andropause titled His Change of Life: Male Menopause and Healthy Aging with Testosterone.
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Title Annotation:Polycystic ovarian syndrome
Author:Wood, Sara G.
Publication:Townsend Letter
Article Type:Report
Geographic Code:1USA
Date:Apr 1, 2013
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